Ucf-101 alleviates Ischaemia/Reperfusion induced retinal inflammation and injury via suppressing oxidative damage.

The Omi/HtrA2 inhibitor 5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (Ucf-101) has shown neuroprotective effects in the central nervous system. However, whether Ucf-101 can protect retinal ganglion cells (RGCs) after retinal ischemia/reperfusion (IR) has not been investigated. We aimed to investigate the effects of Ucf-101 on RGCs apoptosis and inflammation after IR-induced retinal injury in mice. We injected Ucf-101 into the mouse vitreous body immediately after IR injury. After 7 days, hematoxylin and eosin staining was conducted to assess retinal tissue damage. Next, retrograde labeling with FluoroGold, counting of RGCs and TUNEL staining were conducted to evaluate apoptosis. Immunohistochemistry, immunofluorescence staining, and western blotting were conducted to analyze protein levels. IR injury-induced retinal tissue damage could be prevented by Ucf-101 treatment. The number of TUNEL-positive RGCs was reduced by Ucf-101 treatment in mice with IR injury. Ucf-101 treatment inhibited the upregulation of Bax, cleaved caspase-3 and cleaved caspase-9 and activated the JNK/ERK/P38 signaling pathway. Furthermore, Ucf-101 treatment inhibited the upregulation of glial fibrillary acidic protein (GFAP), vimentin, Iba1 and CD68 in mice with IR injury. Ucf-101 prevents retinal tissue damage, improves the survival of RGCs, and suppresses microglial overactivation after IR injury. Ucf-101 might be a potential target to prevent RGCs apoptosis and inflammation in neurodegenerative eye diseases.

Effect of high-frequency oscillation on reduction of atelectasis in perioperative patients: a prospective randomized controlled study.

BACKGROUND: Atelectasis affects approximately 90% of anaesthetized patients, with laparoscopic surgery and pneumoperitoneum reported to exacerbate this condition. High-frequency oscillation therapy applies continuous positive pressure pulses to oscillate the airway, creating a pressure difference in small airways obstructed by secretions. This process helps reduce peak airway pressure, open small airways, and decrease atelectasis incidence, while also facilitating respiratory tract clearance. This study examines the efficacy of high-frequency oscillation on reduction of atelectasis in laparoscopic cholecystectomy (LC) patients under general anaesthesia, evaluated using lung ultrasound. METHODS: Sixty-four patients undergoing laparoscopic cholecystectomy were randomly divided into a control group and a high-frequency oscillation (HFO) group. Both groups underwent total intravenous anaesthesia under invasive arterial monitoring. The HFO group received a 10-minute continuous high-frequency oscillation therapy during surgery, while the control group received no intervention. Lung ultrasound evaluations were performed three times: five minutes post-intubation (T1), at the end of the surgery (T2), and before leaving the Post-Anaesthesia Care Unit (PACU; T3). Blood gas analysis was performed twice: prior to induction with no oxygen supply and before PACU discharge (oxygen supply off). RESULTS: The HFO group displayed a significantly lower incidence of atelectasis at T3 (57.5% vs. 90.3%, OR 6.88, 95%CI (1.74 to 27.24)) compared to the control group. Moreover, the HFO group's PaO2 levels remained consistent with baseline levels before PACU discharge, unlike the control group. Although there was no significant difference in LUS scores between the groups at T1 (8.56 ± 0.15 vs. 8.19 ± 0.18, p = 0.1090), the HFO group had considerably lower scores at T2 (13.41 ± 0.17 vs.7.59 ± 0.17, p < 0.01) and T3 (13.72 ± 0.14 vs.7.25 ± 0.21, p < 0.01). CONCLUSION: Our study indicates that high-frequency oscillation effectively reduces atelectasis in patients undergoing laparoscopic cholecystectomy. Additionally, it can mitigate the decline in oxygen partial pressure associated with atelectasis.

Association of glyphosate exposure with multiple adverse outcomes and potential mediators.

Glyphosate (GLY) is a widely used herbicide with potential adverse effects on public health. However, the current epidemiological evidence is limited. This study aimed to investigate the potential associations between exposure to GLY and multiple health outcomes. The data on urine GLY concentration and nine health outcomes, including type 2 diabetes mellitus (T2DM), hypertension, cardiovascular disease (CVD), obesity, chronic kidney disease (CKD), hepatic steatosis, cancers, chronic obstructive pulmonary disease (COPD), and neurodegenerative diseases (NGDs), were extracted from NHANES (2013-2016). The associations between GLY exposure and each health outcome were estimated using reverse-scale Cox regression and logistic regression. Furthermore, mediation analysis was conducted to identify potential mediators in the significant associations. The dose-response relationships between GLY exposure with health outcomes and potential mediators were analyzed using restricted cubic spline (RCS) regression. The findings of the study revealed that individuals with higher urinary concentrations of GLY had a higher likelihood of having T2DM, hypertension, CVD and obesity (p < 0.001, p = 0.005, p < 0.001 and p = 0.005, respectively). In the reverse-scale Cox regression, a notable association was solely discerned between exposure to GLY and the risk of T2DM (adjusted HR = 1.22, 95% CI: 1.10, 1.36). Consistent outcomes were also obtained via logistic regression analysis, wherein the adjusted OR and 95% CI for T2DM were determined to be 1.30 (1.12, 1.52). Moreover, the present investigation identified serum high-density lipoprotein cholesterol (HDL) as a mediator in this association, with a mediating effect of 7.14% (p = 0.040). This mediating effect was further substantiated by RCS regression, wherein significant dose-response associations were observed between GLY exposure and an increased risk of T2DM (p = 0.002) and reduced levels of HDL (p = 0.001). Collectively, these findings imply an association between GLY exposure and an increased risk of T2DM in the general adult population.

LECT2 Ameliorates Blood-Retinal Barrier Impairment Secondary to Diabetes Via Activation of the Tie2/Akt/mTOR Signaling Pathway.

Purpose: Current treatments for diabetic retinopathy (DR) have considerable limitations, emphasizing the need for new therapeutic options. The effect of leukocyte cell-derived chemotaxin 2 (LECT2) on diabetes-induced blood-retinal barrier impairment and the possible underlying mechanism were investigated both in vivo and in vitro. Methods: Twenty diabetic and 22 nondiabetic eyes were included in this study. Additionally, we established a streptozotocin-induced diabetic mouse model and observed vascular leakage in mice treated with or without recombinant LECT2 (rLECT2) intravitreal injection (40 µg/mL, 1 µL). The levels of LECT2 and interendothelial junction proteins (ZO1, VE-cadherin, and occludin) were analyzed by western blot and/or immunofluorescence. Endothelial junctions in mouse retinas were observed by transmission electron microscopy (TEM). Moreover, confluent human retinal microvascular endothelial cells (HRMECs) and human umbilical vein endothelial cells (HUVECs) were treated (0-72 hours) with glucose (0 or 30 mM) in the presence or absence of rLECT2 (40-360 ng/mL). After treatment, intact cell monolayers were monitored for permeability to 40-kD FITC-dextran. Interendothelial junction targets and Tie2/Akt/mTOR signaling pathway components were investigated by western blot. Results: In diabetic human and mouse retinas and high-glucose (30 mM)-treated HRMECs and HUVECs, the levels of LECT2 and interendothelial junction proteins were decreased. rLECT2 treatment (80 ng/mL) significantly attenuated the hyperglycemia-induced reduction in endothelial cell barrier function and inhibited the migration and tube formation of HRMECs and HUVECs. In addition, rLECT2 increased the levels of interendothelial junction proteins via activation of the Tie2/Akt/mTOR signaling pathway. Furthermore, intravitreal rLECT2 injections increased the levels of interendothelial junction proteins and reversed diabetes-induced junction disruption. Conclusions: rLECT2 can increase the levels of interendothelial tight junction proteins through activation of the Tie2/Akt/mTOR signaling pathway and can ameliorate inner blood-retinal barrier impairment secondary to diabetes. LECT2 might be a potential target to prevent the progression of DR.

Markers of the sympathetic, parasympathetic and sensory nervous system are altered in the human diabetic choroid.

BACKGROUND: We sought to evaluate alterations in markers of the autonomic nervous system in human diabetic choroid. METHODS: Eighteen eyeballs from subjects with diabetes and 22 eyeballs from subjects without diabetes were evaluated in this study. Synaptophysin, tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DßH), neuronal nitric oxide synthase (nNOS), choline acetyltransferase (ChAT), vesicular monoamine transporter II (VMAT-2), vesicular acetylcholine transporter (VAChT), vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), and calcitonin gene-related peptide (CGRP) levels were detected by western blot analysis and immunofluorescence was performed in some cases. Furthermore, differences in adrenergic (α1- and ß2-subtypes) and cholinergic (M1 and M3) receptor levels between diabetic subjects and controls were noted. RESULTS: Decreased synaptophysin levels were found in diabetic choroids by western blot analysis and a reduction of synaptophysin-immunoreactive nerves was also found by immunofluorescence. Furthermore, a decrease of the levels of the key enzyme (TH) and transporter (VMAT2) of norepinephrine was evident both by western blot analysis and immunofluorescence. Additionally, increased NPY, VAChT, nNOS, and CGRP levels were observed in diabetic choroids. The levels of adrenergic (ß2 subtype) and acetylcholine (M1 subtype) receptors decreased in diabetic choroids, as shown by western blotting and although the differences in α1 and M3 were not significant, there was a downward trend. CONCLUSIONS: In the diabetic choroid, the levels of neurotransmitters, enzymes, and receptors associated with choroidal blood flow regulation are altered. These changes may affect the regulation of choroidal blood flow and may be associated with impaired retinal function and retinal pathology.

Restoring VTA DA neurons excitability accelerates emergence from sevoflurane general anesthesia of anxiety state.

Preoperative anxiety is common and often comes with a higher probability of worse recovery. However, the neurological mechanism of the effect of preoperative anxiety on general anesthesia and subsequent awakening remains unknown. In this study, we report an anxious state results in delayed awakening in anxiety model mice from sevoflurane general anesthesia. More profound inhibition of DA neurons in the VTA contributes to delayed awakening. Optogenetic stimulation of VTA DA neurons can reverse the delay. The results indicate that VTA DA neurons may be involved in the delay in awakening from general anesthesia caused by anxiety.